EP1935882B1 - Composés bicycliques - Google Patents

Composés bicycliques Download PDF

Info

Publication number
EP1935882B1
EP1935882B1 EP08005358A EP08005358A EP1935882B1 EP 1935882 B1 EP1935882 B1 EP 1935882B1 EP 08005358 A EP08005358 A EP 08005358A EP 08005358 A EP08005358 A EP 08005358A EP 1935882 B1 EP1935882 B1 EP 1935882B1
Authority
EP
European Patent Office
Prior art keywords
phenyl
methyl
indol
hydroxyethylamino
ethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP08005358A
Other languages
German (de)
English (en)
Other versions
EP1935882A1 (fr
Inventor
Shiro Miyoshi
Kohei Ogawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asahi Kasei Pharma Corp
Original Assignee
Asahi Kasei Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Kasei Pharma Corp filed Critical Asahi Kasei Pharma Corp
Publication of EP1935882A1 publication Critical patent/EP1935882A1/fr
Application granted granted Critical
Publication of EP1935882B1 publication Critical patent/EP1935882B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel compounds which are useful as a medicine for treating and preventing diabetes, obesity, hyperlipidemia, digestive diseases, depression, fatty liver or urinary incontinence.
  • Beta-adrenoreceptors were classified into ⁇ 1-, ⁇ 2- and ⁇ 3-adrenoreceptor, and it was recognized that stimulation of ⁇ 1 induces an increase in the heart rate and stimulation of ⁇ 2 induces a relaxation of the smooth muscle tissue, thereby resulting in lowering the blood pressure. It was also recognized that stimulation of ⁇ 3 facilitates the lipolysis in adipocytes and increases thermogenesis. Therefore, ⁇ 3-agonist have been shown to be useful as a medicine for treating and preventing diabetes, obesity and hyperlipidemia ( Nature, vol. 309, pp. 163-165, 1984 ; Int. J. Obes. Relat. Metab. Disord., vol. 20, pp.
  • ⁇ 3-adrenoreceptor is expressed in the detrusor and a ⁇ -agonist induces a relaxation of the detrusor J. Urinol., vol. 161, pp. 680-685, 1999 ; J. Pharmacol. Exp. Ther., vol. 288, pp. 1367-1373, 1999 ). Therefore, ⁇ 3-agonists are expected to be useful as a medicine for treating and preventing urinary incontinence.
  • Some compounds showing a ⁇ 3-agonist activity have been known. Compounds having high selectivity or having low ⁇ 1- and ⁇ 2-stimulating activities are particularly required when their usefulness as a medicine is taken into consideration. This is because compounds having both ⁇ 1- and ⁇ 2-stimulating activities induce side effects such as increase in the heart rate and lowering of the blood pressure, as set forth above.
  • the compound described in EP 171702 and having the following structural formula has been known as having heart rate-increasing activity, myocardial contraction enhancement and antiobestic activity.
  • this compound acts on the heart and is different from the compound of the present invention in terms of its chemical structure and in that the former strongly acts on the heart.
  • JP-A-55-53262 and JP-A-58-41860 and having the following structural formula: is known as having a, ⁇ 3-blocking activity, namely the effect of lowering blood pressure; and the compound described in DE 2651572 and having the following structural formula: is known as having vasodilator action.
  • these compounds are different from the compounds of the present invention in terms of their chemical structures and intended uses.
  • the present inventors formerly invented compounds having excellent ⁇ 3-agonist activity and disclosed compounds represented by, for example, the following structural formula in WO 97/25311 .
  • the above compounds are different from the compounds of the present invention in their chemical structures.
  • the present inventors synthesized a variety of compounds and studied their activities. As a result, the inventions disclosed in the abovementioned WO 01/83451 were completed. It was thought, however, that there was a need to provide further useful compounds. The present inventors have earnestly studied and synthesized many more compounds. As a result, the present inventors have found that a novel bicyclic compound of the general formula (I) set forth below, has selective ⁇ 3-agonist activity and that it can exhibit sufficient hypoglycemic and lipolytic activities with high safety and further has anti-urinary incontinence activity due to a relaxation of the detrusor, completes the present invention.
  • a novel bicyclic compound of the general formula (I) set forth below has selective ⁇ 3-agonist activity and that it can exhibit sufficient hypoglycemic and lipolytic activities with high safety and further has anti-urinary incontinence activity due to a relaxation of the detrusor, completes the present invention.
  • the present invention includes the following inventions.
  • halogen atom as used herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • (C 1 -C 6 )alkyl group means a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms and specifically means methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl or the like.
  • (C 3 -C 6 )cycloalkyl group means a cyclic saturated hydrocarbon group containing from 3 to 6 carbon atoms and specifically means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • R 1 represents a hydrogen atom, a hydroxyl group or a halogen atom. Examples thereof include a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferred examples thereof include a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom and a bromine atom.
  • the position on the benzene ring at which R 1 is attached is not limited, the position is preferably ortho- or para-position with respect to the aminoethanol side-chain, with para-position (2-position) being particularly preferred.
  • R 2 represents NHSO 2 R 3 or SO 2 NR 4 R 4' , wherein R 3 represents an alkyl group containing from 1 to 6 carbon atoms, a benzyl group, a phenyl group or NR 4 R 4' and wherein R 4 and R 4' may be the same or different and each independently represents a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms.
  • R 2 include NHSO 2 CH 3 , NHSO 2 C 2 H 5 , NHSO 2 C 6 H 5 , NHSO 2 CH 2 C 6 H 5 , SO 2 NHCH 3 , SO 2 NHC 2 H 5 , NHSO 2 N(CH 3 ) 2 and NHSO 2 N(C 2 H 5 ) 2 .
  • Particularly preferred examples include NHSO 2 CH 3 , SO 2 NHCH 3 and NHSO 2 N(CH 3 ) 2 .
  • R 1 and R 2 within the combinations of R 1 and R 2 , the combination in which R 1 is a hydrogen, fluorine atom, chlorine atom or bromine atom at para-position (2-position) and R 2 is NHSO 2 CH 3 or NHSO 2 N(CH 3 ) 2 is preferred.
  • R 1 is a hydroxyl group at para-position (2-position) and R 2 is SO 2 NHCH 3 is also preferred.
  • R 5 and R 51 are a hydrogen atom or a (C 1 -C 6 )alkyl group. Examples thereof include a hydrogen atom, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neopentyl and n-hexyl, with a hydrogen atom, methyl or ethyl being preferred.
  • All of Z 1 to Z 6 represent a carbon atom
  • R 6 is any one of 3-pyridyl, 4-pyridyl, 3-piperidinyl, N-tert-butoxycarbonyl-3-piperidinyl, 2-ethoxycarbonylethyl, 2-(N,N-dimethylaminocarbonyl)ethyl and 2-acetylaminoethyl and R 7 is methyl or ethyl when all of Z 1 to Z 6 represent a carbon atom. Particularly preferably, R 7 is methyl. Further, when Z 2 is a nitrogen atom and Z 1 and Z 3 to Z 6 represent a carbon atom, R 6 may be absent and R 7 may be methyl, ethyl, methoxy or the like, with methyl being preferred.
  • the "substituent" which may exist on the "optionally substituted -(CH 2 ) n -phenyl group” is a hydroxyl group, a halogen atom, a trifluoromethyl group, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkoxy group, a (C 1 -C 6 )acyl group, NR 4 R 4' , NHCO(C 1 -C 6 )alkyl, NHCH 2 C 6 H 5 , NHSO 2 (C 1 -C 6 )alkyl, NHSO 2 CH 2 C 6 H 5 , a nitro group or a cyano group.
  • the number of the substituents on the phenyl group is from 1 to 5, and preferably from 1 to 2. Although the position of substitution is not particularly limited, the position is preferably meta-position with respect to (CH 2 ) n .
  • Preferred examples of the substituent include a methoxy group and a hydroxyl group.
  • R 4 and R 4' contained in R 3 , R 9 and the substituent on the optionally substituted -(CH 2 ) n -phenyl group are as defined above and may be the same or different.
  • R 5 contained in R 3 , R 8 and R 9 is as defined above and may be the same or different.
  • R 6 and/or R 7 is an imidazolyl, triazolyl or tetrazolyl
  • one or more ring carbon atoms of the each heterocyclic ring may be independently optionally substituted with one or more substituents which are independently selected from a hydrogen, a (C 1 -C 6 )alkyl group optionally substituted with one or more halogen atoms, a halogen atom, nitro, cyano and -(CH 2 ) n -R 9 wherein R 9 is as defined above.
  • substituents means "from 1 to a" substituents wherein a is defined as the number of all positions on which a substituent can exist (i.e.
  • each substituent and the combination of substituents are not limited, preference is given to the case in which there is no substituent (i.e. all of the substituents being a hydrogen atom) or to the case in which there are two or more substituents and one of them is a halogen atom or a methyl group and the others are hydrogen atoms.
  • X represents NR 10 wherein R 10 represents a hydrogen atom, a -(CH 2 ) n -phenyl group optionally substituted with a hydroxyl group, a halogen atom, a trifluoromethyl group, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkoxy group, a (C 1 -C 6 )acyl group, NR 4 R 4' , NHCO(C 1 -C 6 )alkyl, NHCH 2 C 6 H 5 , NHSO 2 (C 1 -C 6 ) alkyl, NHSO 2 CH 2 C 6 H 5 , a nitro group or a cyano group, a -(C 1 -C 10 )alkyl group or a -(CH 2 ) n -R 8 wherein R 8 , R 4 and R 4' are as defined above, with NH, an oxygen atom or a sulfur atom being preferred. Further,
  • Y represents an oxygen atom, NH, a sulfur atom or a methylene group, with an oxygen atom, NH or a sulfur atom being preferred. Further, Y is more preferably an oxygen atom or NH.
  • *1 is an asymmetric carbon atom
  • *2 is also an asymmetric carbon atom when R 5 is a (C 1 -C 6 )alkyl group.
  • the compound of the general formula (I) can be in the form of four isomers, that is to say (R,R), (R,S), (S,S) and (S,R) which are each described in order of *1 and *2.
  • R 5 is a hydrogen atom
  • two isomers can exist. Not only optically pure isomers, but also mixtures of two isomers with any mixing ratio encompassed by the present invention. Further, optional mixtures of three isomers and the mixture of all the four isomers are also encompassed by the present invention. From the viewpoint of the expression of pharmacological activity, a preferred configuration of the asymmetric carbon *1 is the configuration R.
  • illustrative examples of specific compounds of the present invention represented by the general formula (I) wherein Z 1 represents a carbon atom and Z 2 to Z 6 represent a carbon atom include:
  • an objective compound of the general formula (I) may be prepared by, as the first step, reacting a compound represented by the general formula (II): wherein W represents a hydrogen atom or an amino-protecting group, and R 5 , R 6 , R 7 , X, Y, Z 1 to Z 6 and *2 are each as defined above, with a compound represented by the general formula (III): wherein R 1' represents a hydrogen atom, OA 1 (wherein A 1 represents a hydroxyl-protecting group) or a halogen atom, R 2' represents NW 2 SO 2 R 3 or SO 2 NR 4 R 4' , W 2 represents a hydrogen atom or an amino-protecting group, L 2 represents a leaving group, and R 3 , R 4 and R 4' are each as defined above, to give an amino ketone (-CO-CH 2 -N
  • L 2 examples include a chlorine atom, a bromine atom, an iodine atom and the like.
  • W and W 2 represent an amino-protecting group
  • the amino-protecting group is not limited as long as it is a protecting group used in a common organic synthesis.
  • Preferred examples of the amino-protecting group include a benzyl group, a substituted benzyl group and the like.
  • R 1' is OA 1
  • the hydroxyl-protecting group A 1 is also not limited as long as it is a protecting group used in a common organic synthesis.
  • Preferred examples of the hydroxyl-protecting group include a benzyl group, a substituted benzyl group and the like.
  • the amount of the compound represented by the general formula (II) to be used in the first step is from 1 to 5 mol for 1 mol of the compound represented by the general formula (III).
  • a base may be added to neutralize an acid generated by the reaction.
  • the base to be used include organic bases such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydrogencarbonate and sodium hydroxide and the like.
  • compounds of the general formula (II) may be used also in the form of their salts, provided that the abovementioned base is added.
  • Examples of the solvent to be used in the reaction include lower alcohols such as methanol, ethanol and isopropyl alcohol, chlorinated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, with dimethylformamide being preferred.
  • reaction temperatures and reaction times are not limited, the reaction is carried out at a temperature of from -30°C to the boiling point of the selected solvent, preferably a temperature of from 0°C to 30°C, for 10 minutes to 24 hours.
  • the amino ketone compound generated in the first step may be used in the reductive reaction of the second step without isolation from the reaction mixture. However, the amino ketone compound may be optionally extracted and purified before the reductive reaction.
  • the reducing agent to be used include sodium borohydride, sodium cyanoborohydride, borane and the like.
  • the solvent to be used in the reaction include lower alcohols such as methanol, ethanol and isopropyl alcohol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, with ethanol and dimethylformamide being preferred.
  • reaction temperatures and reaction times are not limited, the reaction is carried out at a temperature of from - 30°C to the boiling point of the selected solvent, preferably a temperature of from 0°C to 30°C, for 10 minutes to 24 hours.
  • the removal of the amino-protecting group and/or hydroxyl-protecting group may be removed under reaction conditions usually used for removing the protecting groups to be used.
  • a benzyl or substituted benzyl group is used as the protecting group, it may be removed, for example, by a hydrogenation reaction using palladium/activated carbon as a catalyst.
  • racemic mixture Compounds represented by the general formula (I), which contain asymmetric carbons represented by *1 and *2, are obtained as a racemic mixture by the process set forth above.
  • the racemic mixture can be optically resolved into optically active substances by converting the racemic mixture to acid addition salts with an optically active acid such as camphorsulfonic acid or mandelic acid followed by a fractional crystallization treatment.
  • the racemic mixture may be also optically resolved using a commercially available optically active column.
  • optically active substances may be also obtained by carrying out an asymmetric reduction treatment with a hydrogen donating compound in the presence of an asymmetric reduction catalyst in the second step according to the process described in WO 00/58287 .
  • an objective compound of the general formula (I) may be prepared by, as the first step, reacting a compound represented by the general formula (II) with a compound represented by the general formula (IV): wherein L 2 represents a leaving group, A 2 represents a hydroxyl-protecting group, and R 1' , R 2' and *1 are as defined above, to give an amino ether (-CHOA 2 -CH 2 -NHW-) compound; and, as the second step, removing the hydroxyl-protecting group A 2 , optionally removing the hydroxyl-protecting group A 1 , and when W and W 2 are not hydrogen atoms but amino-protecting groups, removing them.
  • Examples of the leaving group L 2 include a chlorine atom, a bromine atom, an iodine atom and the like, with an iodine atom being preferred.
  • W and W 2 are as set forth above in Preparation Process 1.
  • the hydroxyl-protecting group A 1 when R 1' is OA 1 is also as set forth above in Preparation Process 1.
  • Another hydroxyl-protecting group A 2 is also not limited as long as it is a protecting group used in a common organic synthesis.
  • Preferred examples of the hydroxyl-protecting group A 2 include a triethylsilyl group.
  • the amount of the compound represented by the general formula (II) to be used is from 1 to 1.5 mol for 1 mol of the compound represented by the general formula (IV).
  • a base may be added to neutralize an acid generated by the reaction. Examples of the base to be used include triethylamine, diisopropylethylamine and the like. Further, compounds of the general formula (II) may be used also in the form of their salts, provided that the abovementioned base is added.
  • reaction temperature and reaction time are not limited, the reaction is carried out at a temperature of from 0°C to 90°C, preferably a temperature of 60°C, for 10 minutes to 24 hours.
  • the hydroxyl-protecting group A 2 and optionally the other protecting groups may be removed under reaction conditions usually used for removing the protecting groups to be used.
  • a triethylsilyl group as A 2 may be removed using, for example, tetrabutylammonium fluoride.
  • Optically active substances may be prepared as set forth above in Preparation Process 1 by formation of acid addition salts with an optically active acid followed by a fractional crystallization treatment, or optical resolution using a commercially available optically active column or the like.
  • an optically active compound represented by the general formula(I) may be also prepared using an optically active compound represented by the general formula (IV) prepared according to the processes described in, for example, WO 97/25311 and WO 01/04092 , and a compound represented by the general formula (II) wherein R 5 is a hydrogen atom.
  • an objective compound of the general formula (I) may be prepared by reacting a compound represented by the general formula (V): wherein L 3 represents a hydroxyl group or a leaving group, and R 1' , R 2' , R 5 , A 2 , W, *1 and *2 are as defined above, with a compound represented by the general formula (VI): wherein Y represents an oxygen atom or a sulfur atom, and R 6 , R 7 , X and Z 1 to Z 6 are as defined above; and, as the second step, removing the hydroxyl-protecting group A 2 , optionally removing the hydroxyl-protecting group A 1 , and when W and W 2 are not hydrogen atoms but amino-protecting groups, removing them.
  • Examples of the leaving group L 3 include a chlorine atom, a bromine atom, an iodine atom and the like, with bromine atom being preferred.
  • Compounds represented by the general formula (II) wherein Y is an oxygen atom may be prepared by the process set forth below. That is, an objective compound may be obtained by reacting a compound represented by the general formula (VI): wherein Y represents an oxygen atom, and R 6 , R 7 , X and Z 1 to Z 6 are as defined above, with a compound represented by the general formula (VII): wherein L 1 represents a leaving group, W 1 represents an amino-protecting group, and R 5 and *2 are as defined above, in the presence of a base; as the second step, removing the amino-protecting group W 1 ; and, as the final step, optionally re-protecting this amino group with another protecting group W.
  • W is a hydrogen atom (i.e. the amino group is in the free form)
  • the compound may be used in the following reaction.
  • the leaving group L 1 include a chlorine atom, a bromine atom, an iodine atom and the like.
  • the amino-protecting group W 1 is not limited as long as it is a protecting group used in a common organic synthesis. Preferred examples include a benzyloxycarbonyl group, a substituted benzyloxycarbonyl group, a tert-butoxycarbonyl group and the like.
  • W may be selected as set forth above in Preparation Process 1 for compounds of the formula (I).
  • the amount of the compound represented by the general formula (VII) to be used in the first step is from 1 to 5 mol for 1 mol of the compound represented by the general formula (VI).
  • the base to be used include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, triethylamine and the like.
  • the solvent to be used in the reaction include tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and the like.
  • reaction temperature and reaction time are not limited, the reaction is carried out at a temperature of from 0°C to the boiling point of the selected solvent, preferably from room temperature to 90°C, for 10 minutes to 24 hours.
  • the amino-protecting group W 1 may be removed under reaction conditions usually used for removing the protecting group to be used.
  • a benzyloxycarbonyl or substituted benzyloxycarbonyl group it may be removed, for example, by a hydrogenation reaction using palladium/activated carbon as a catalyst.
  • a tert-butoxycarbonyl group it may be removed using an acid such as trifluoroacetic acid or hydrochloric acid.
  • Compounds represented by the general formula (II) wherein Y is a sulfur atom may be prepared by the process set forth below. That is, an objective compound may be obtained by reacting a compound represented by the general formula (VI): wherein Y represents a sulfur atom, and R 6 , R 7 , X and Z 1 to Z 6 are as defined above, with a hydrochloride or hydrobromide salt of a compound represented by the general formula (VII): wherein W 1 represents a hydrogen atom, L 1 represents a chlorine atom or a bromine atom, and R 5 and *2 are as defined above.
  • the amount of the compound represented by the general formula (VII) to be used is from 1 to 1.5 mol for 1 mol of the compound represented by the general formula (VI).
  • the reaction is usually carried out in the presence of a base.
  • the base include organic bases such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydrogencarbonate and sodium hydroxide and the like.
  • Examples of the solvent to be used in the reaction include lower alcohols such as methanol, ethanol and isopropyl alcohol, acetic acid, chlorinated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, which may be used alone or as a mixed solvent comprising plural solvents.
  • a mixed solvent of tetrahydrofuran and methanol is used.
  • reaction temperature and reaction time are not limited, the reaction is carried out at a temperature of from -30°C to the boiling point of the selected solvent, preferably a temperature of from 0°C to 30°C, for 10 minutes to 24 hours.
  • a compound represented by the general formula (II'): wherein R 5 , R 6 , R 7 , X, Z 1 to Z 6 , W and W 3 are as defined above, may be obtained by, as the second step, removing the amino-protecting group W 1 , and, as the final step, optionally re-protecting this amino group with another protecting group W.
  • the triflate compound of the general formula (VIII) may be obtained by applying reaction conditions commonly used for converting a hydroxyl group into a triflate group to a compound of the general formula (VI) wherein Y is an oxygen atom.
  • the amino-protecting group W 1 is not limited as long as it is a protecting group used in a common organic synthesis. Preferred examples include a benzyloxycarbonyl group, a substituted benzyloxycarbonyl group, a tert-butoxycarbonyl group and the like.
  • the amino-protecting group W 3 is not limited as long as it is a protecting group used in a common organic synthesis. Preferred examples include a benzyl group, a substituted benzyl group and the like.
  • the compound having the amino-protecting group W 3 is more preferably provided for the next reaction in the protected form without removing the amino-protecting group W 3 than in the form of free amine obtained by removing the amino-protecting group W 3 .
  • the compound in which W is a hydrogen atom i.e. the amino group being in the free form
  • W may be selected as set forth above in Preparation Process 1 for compounds of the general formula (I).
  • the amino-protecting group W 1 may be removed under reaction conditions usually used for removing the protecting group to be used.
  • a compound represented by the general formula (VI) may be obtained by removing the protecting group A 1 under a commonly used condition.
  • a compound represented by the general formula (X) may be commercially available, or may be synthesized by the process described in WO 94/29290 or according to the processes described in the following literatures.
  • X NH
  • Z 1 represents a nitrogen atom or a carbon atom
  • Z 2 to Z 6 represent a carbon atom
  • R 6 an alkyl group or an aryl group
  • a compound represented by the general formula (XI) may be synthesized by the process described in the literature ( R. Gastpar et al., J. Med. Chem., vol. 41, No. 25, pp. 4965-4972, 1998 ) or the literature ( K. Cardwell et al., J. Am. Chem. Soc., vol. 110, pp. 2242-2248, 1988 ).
  • the present compounds and the starting compounds and intermediates for preparing each of the present compounds which can be obtained as set forth above may be isolated and purified by the conventional means such as extraction, crystallization, distillation, chromatography, recrystallization or the like.
  • Salts of a compound of the general formula (I) according to the present invention may be a known salt, and examples thereof include hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate and the like, and acid addition salts with an optically active acid such as camphorsulfonic acid, mandelic acid or substituted mandelic acid. Among them, pharmaceutically acceptable salts are particularly preferred.
  • an acid addition salt of the compound can be obtained by dissolving the compound in alcohol such as methanol or ethanol, to which the equivalent amount to several times amount of the acid component is then added.
  • the acid component to be used may be a pharmaceutically acceptable mineral or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogensulfate, dihydrogen phosphate, citric acid, maleic acid, tartaric acid, fumaric acid, gluconic acid or methanesulfonic acid.
  • ⁇ 3-receptor associated diseases are useful as medicines.
  • the compounds, which have ⁇ 3-receptor agonist activities can be used as a medicine for treating and preventing ⁇ 3-receptor associated diseases.
  • ⁇ 3-receptor associated disease is a generic expression for diseases which can be improved by agonistic effects mediated by ⁇ 3-receptor. Examples of ⁇ 3-receptor associated diseases include diabetes, obesity, hyperlipidemia, fatty liver, digestive diseases (preferably dyskinesia of digestive system or ulcer) and depression.
  • the compound can be used as a medicine for treating and preventing fatty liver, urinary incontinence and others.
  • Urinary incontinence is defined by International Incontinence Society as a condition which is objectively demonstrable involuntary urine leakage and causes a social or hygienic problem.
  • Compounds of the present invention are safe compounds with a low acute toxicity. Further, compounds of the present invention are characterized, for example, in that they do not inhibit some of drug metabolizing enzymes (cytochrome P-450). Methods for determining whether cytochrome P-450 may be inhibited or not include known methods described, for example, in the literature ( Crespi C.L. et al., Analytical Biochemistry, vol. 248, pp. 188-190, 1997 ).
  • a medicine of the present invention is preferably prepared in the form of a pharmaceutical composition by optionally adding a pharmaceutically acceptable carrier to an effective amount of a compound represented by the general formula (I) or a salt thereof.
  • pharmaceutically acceptable carriers include excipients, binders such as carboxymethylcellulose, disintegrators, lubricants, auxiliaries and the like.
  • a compound of the present invention When a compound of the present invention is administered to humans, it can be orally administered in the form of tablet, powder, granule, capsule, sugar-coated tablet, solution, syrup or the like. Further, it can be parenterally administered in the form of injection or the like.
  • the dosage will vary dependent on the age and weight of the patient and the extent of disease, the daily dosage for an adult is usually from 0.01 to 2000 mg, which is singly administered or is divided into several dosages and then administered.
  • the duration of administration can vary between several weeks and several months and the everyday medication is usually applied. However, the daily dosage and duration of administration can be increased or decreased from the above ranges dependent on the conditions of patient.
  • Fast atom bombardment mass spectrum was determined with a JMS-AX500 type mass spectrometer manufactured by JEOL. LTD or a JMS-SX102 type mass spectrometer manufactured by JEOL. LTD.
  • the matrix used was 3-nitrobenzyl alcohol.
  • the mass spectrometer used was a Platform-LC type mass spectrometer manufactured by Micromassm (England).
  • a compound to be analyzed was ionized by erectrospray (ESI) method.
  • the liquid chromatograph used was that manufactured by GILSON (France).
  • the separation column used was Mightysil RP-18 GP 50-4.6 (product number 25468-96) manufactured by KANTO KAGAKU (Japan).
  • the eluting conditions are as follows.
  • TLC thin layer chromatography
  • a purifying process with silica gel column was carried out using silica gel 60 manufactured by Merck (Germany).
  • An objective compound was eluted with a mixed solvent (n-hexane/ethyl acetate or chloroform/methanol).
  • a purifying process with reversed phase column was carried out using a YMC CombiPrep ODS-A CCAAS05-0520WT type column manufactured by YMC (Japan).
  • An objective compound was eluted by gradient elution using water/acetonitrile (containing 0.1%(v/v) acetic acid). The detailed eluting conditions are as follows.
  • N-(3-acetyl-4-chlorophenyl)methanesulfonamide 300 mg was dissolved in dioxane (5 mL), and bromine (77 ⁇ L) was added dropwise with ice-cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was washed with a water/ethanol mixture (1:1) and then dried under reduced pressure to yield N-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide (312 mg) as a colorless crystal.
  • N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g) as a crude product.
  • the whole quantity of the crude product was dissolved in ethanol (40 mL), and zinc dust (20 g) was added. After further adding concentrated hydrochloric acid (2 mL), the mixture was heated to reflux for 4 hours. The reaction mixture was filtered. To the filtrate, ethyl acetate (100 mL) was added. The resulting mixture was washed with water (100 mL) three times and the organic layer was dried over anhydrous magnesium sulfate.
  • the diazonium salt solution was gradually added to a solution of cuprous chloride (0.95 g) in concentrated hydrochloric acid (10 mL) at room temperature. After foaming was over, the reaction mixture was stirred at 80°C for 30 minutes and then allowed to cool down to room temperature. Water (60 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL) three times and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
  • N-(3-acetyl-5-chlorophenyl)methanesulfonamide 500 mg was dissolved in dioxane (10mL). The temperature was maintained at 50°C and bromine (0.11 mL) was added. After stirring for 30 minutes, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with water (50 mL) twice and then dried over anhydrous magnesium sulfate.
  • Lithium aluminium hydride (216 mg) was suspended in THF (20 mL), and the compound (573 mg; obtained in the step C of Reference Example 9) was gradually added at room temperature. The resulting mixture was heated to 40°C and stirred at the same temperature for 5 minutes. The mixture was then cooled down to 0°C. Water (216 ⁇ L), an aqueous 15% sodium hydroxide solution (216 ⁇ L) and water (648 ⁇ L) were added in this order, and the resulting reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (20:1 chloroform/methanol) to yield the title compound (506 mg).
  • the title compound (4.60 g) was obtained as a crude product from 6-methoxy-3-methyl-1H-indole (3.89 g; synthesized according to the process described in the literature ( Gan et al., J. Org. Chem., vol. 62, pp. 9298-9304, 1997 )), phosphoryl chloride (6.7 mL) and DMF (20 mL).
  • the compound (337 mg; obtained in the step B of Reference Example 10) was dissolved in the mixture of methanol (6 mL) and THF (2 mL), and 10% palladium/carbon powder (177 mg) was added.
  • the atmosphere in the system was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 50 minutes.
  • the catalyst was filtered and the solvent contained in the filtrate was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (333 mg).
  • the title compound (239 mg) was obtained from the compound (330 mg; obtained in the step C of Reference Example 10), boron tribromide (1N solution in methylene chloride, 3.0 mL) and methylene chloride (dehydrated, 6 mL).
  • Pyridine hydrochloride was prepared by carefully mixing pyridine (100 mL) and concentrated hydrochloric acid (100 mL) in a flask equipped with a Liebig condenser and heating the resulting mixture at 180°C with stirring to remove water.
  • the compound (4.50 g; obtained in the step A of Reference Example 11) was added, followed by stirring at 180°C for 2.5 hours.
  • the reaction mixture was poured into ice water and the pH was adjusted to about 5 with an aqueous sodium hydroxide solution, followed by extraction with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate and the solvent was then distilled off under reduced pressure.
  • Ethyl 3-methyl-6-methoxy-1H-indole-2-carboxylate (1.00 g; synthesized according to the disclosures in the literature ( Gan et al., J. Org. Chem., vol. 62, pp. 9298-9304, 1997 ) was dissolved in methylene chloride (dehydrated, 13 mL), and boron tribromide (1 M/methylene chloride, 17.2 mL) was added dropwise under ice-cooling. The resulting mixture was allowed to warm to room temperature and stirred for 40 minutes. The reaction solution was then cooled with ice, followed by addition of water. The resulting mixture was extracted with chloroform, washed with saturated brine and dried over sodium sulfate.
  • the compound (193 mg; obtained in the above step B) was dissolved in THF (5 mL). Acetic acid (115 ⁇ L) and tetra-n-butylammonium fluoride (1.0 M/THF solution, 2.0 mL) were added and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture, a saturated aqueous sodium hydrogencarbonate solution was added. The resulting mixture was extracted with ethyl acetate three times and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (3:1-2:3 hexane/ethyl acetate) to yield the title compound (161 mg).
  • Step D Synthesis of ethyl (R)-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxy]-3-methyl-1H-indole-2-carboxylate hydrochloride
  • the compound (161 mg; obtained in the above step C) was dissolved in ethanol (12 mL) and THF(6 mL). To the resulting solution, 20% palladium hydroxide/carbon powder (50% moisture, 103 mg) was added. After the atmosphere in the system was replaced with a hydrogen atmosphere, the mixture was stirred at 60°C for 80 minutes. The atmosphere in the system was replaced with an argon atmosphere and chloroform (5 mL) was then added. After the resulting mixture was filtered and 0.1 N hydrochloric acid in ethanol (7 mL) was added to the filtrate, the solvent was distilled off under reduced pressure. Chloroform was added to the residue. The deposited solid was then collected by filtration and dried to yield the title compound (96 mg).
  • the compound (47 mg; obtained in Example 1) was dissolved in methanol (10 mL): An aqueous sodium hydroxide solution (2.0 M, 450 ⁇ L) was added and the resulting mixture was stirred at a temperature of 50 to 55°C for 4 hours.
  • the reaction mixture was cooled down to room temperature and 0.1 N hydrochloric acid in ethanol (8 mL) was added.
  • the solvent was distilled off under reduced pressure and water (5 mL) was added to the residue.
  • the solid was collected by filtration and dried to give the title compound (28 mg).
  • Step B Synthesis of ethyl (R)-1-methyl-6-[2-[2-(3-methylsulfonylamino)phenyl-2-hydroxyethylamino]ethoxyl-3-methyl-1H-indole-2-carboxylate hydrochloride
  • the compound (73 mg; obtained in the above step A) was dissolved in ethanol (10 mL) and THF (5 mL). To the resulting solution, 20% palladium hydroxide/carbon powder (50% moisture, 72 mg) was added. After the atmosphere in the system was replaced with a hydrogen atmosphere, the mixture was stirred at 60°C for 2 hours. The atmosphere in the system was replaced with an argon atmosphere and chloroform (5 mL) was then added. After the resulting mixture was filtered and 0.1 N hydrochloric acid in ethanol (7 mL) was added to the filtrate, the solvent was distilled off under reduced pressure. A small amount of chloroform and diethyl ether was added to the residue.
  • the title compound (1.58 g) was obtained from the compound (1.27 g; described in Reference Example 1), the compound (530 mg; obtained in the step B of Reference Example 11), 1,1'-azobis(N,N-dimethylformamide)(860 mg) and triphenylphosphine (1.31 g).
  • Step C Syntheses of (R)-N-[3-[2-[2-(3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide hydrochloride and (R)-N-[3-[2-[2-(1-benzyl-3-methylindazol-6-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide hydrochloride
  • the compound (740 mg; obtained in the above step B) was dissolved in a mixed solvent of TBF (5 mL) and methanol (5 mL). To the resulting solution, 20 % palladium hydroxide/carbon powder (50% moisture, 186 mg) was added. After the atmosphere in the system was replaced with a hydrogen atmosphere, the mixture was stirred at 50°C for 6 hours. The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure.
  • the compound of Example for reference 85 was obtained by purifying 50 mg aliquot of the residue. The remainder of the residue was dissolved in a 0.1 N hydrochloric acid solution in ethanol (13 mL) and 20% palladium hydroxide/carbon powder (50% moisture, 203 mg) was added.
  • Example for reference 84 After the atmosphere in the system was replaced with a hydrogen atmosphere, the mixture was stirred at 50°C for 1 hour. After the generated precipitate was dissolved by adding a small amount of concentrated ammonia water, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol and a 0.1 N hydrochloric acid solution in ethanol was added. The generated crystal was filtered, washed with ether and then dried to yield the compound (274 mg) of Example for reference 84.
  • Human ⁇ 3-agonist activities were determined using CHO (Chinese hamster ovary) cells transfected with pcDNA3 (invitrogen) to which human ⁇ 3 gene had been inserted.
  • Human ⁇ 3 fragment was first obtained from human adipose tissue cDNA (Clonetech) by PCR using the primer of ⁇ 3 ( Krief, et al., J. Clin. Invest., vol. 91, pp. 344-349 (1993 )). The human ⁇ 3 fragment thus obtained was used as a probe to obtain the full length human ⁇ 3 gene from a human genomic library (Clonetech).
  • the above cells were cultured in a Ham F-12 medium supplemented with 10% fetal bovine serum, 400 ⁇ g/mL geneticin (Gibco BRL), 100 U/mL penicillin and 100 ⁇ g/mL streptomycin. After placing these cells (5x10 5 ) into a 6-well plate and culturing them for 24 hours, they were allowed to stand on a serum-free Ham F-12 medium for 2 hours. The compound was first dissolved in DMSO, repeatedly diluted by ten times with Ham F-12 supplemented with 1 mM isobutylmethyl-xanthine and 1 mM ascorbic acid to a final concentration of from 10 -5 to 10 -12 M, and then added to the cells.
  • DMSO DMSO
  • the heart was excised from a male guinea pig weighing 180-250 g to prepare a specimen of the right atrium.
  • the specimen was set in an organ bath filled with a Krebs solution which had been aerated with a mixed gas of 5%CO 2 /95%O 2 .
  • the automaticity was determined using a isometric transducer (NIHON KOHDEN TB-611T) connected to a polygraph (NIHON KOHDEN MR-6000).
  • the present compounds described in the Examples have a higher ED 50 value than that of ⁇ 3. Therefore, these compounds were selective and hardly induce an increase of the heart rate, and are expected to have lower side effects.
  • a transgenic mouse expressing human ⁇ 3 was prepared according to the method reported by Hogan et al. (A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY ) by linking mouse ⁇ 3 promoter to upstream of human ⁇ 3 gene used in Test Example 1. The mouse expressed human ⁇ 3 gene in an organ which expresses mouse ⁇ 3.
  • mice After fasting for four hours, the transgenic mice were orally dosed with a compound of the present invention dissolved in 10% hydroxypropyl- ⁇ -cyclodextrin (Aldrich) at a dose of 0.1 mL/10 g body weight.
  • a blood glucose level was determined by measuring the serum glucose concentration in the sample using Glucose Test B Test Wako (Wako Pure Chemical Industries).
  • a free fatty acid level was measured using NEFA HA Test Wako (Wako Pure Chemical Industries). It was found that the compounds of the present invention exhibit hypoglycemic activity and lipolytic activity while increasing the blood free fatty acid concentration.
  • thermogenesis was measured with an OXYMAX System (Columbus) according to the method reported by Largis et al. (Drug Development Research, vol. 32, pp. 69-76 (1994 )).
  • OXYMAX System Cold-Bassham
  • the measurement of thermogenesis carried out after the oral administration of the compounds of the present invention showed that the compounds of the present invention possess thermogenesis increasing activities.
  • the contraction force of human urinary bladder detrusor was determined according to the method reported by Takeda M. et al. (J. Pharm. Exp. Ther. 288, pp. 1367-1373 (1999 )). That is, the compounds of the present invention were tested for their relaxant effects using the human bladder detrusor in the constricted condition induced by carbachol (0.5x10 -6 M). The fact that the urinary bladder detrusor was allowed to relax by the present compounds at 10 -5 M suggests the effectiveness of the present compounds against urinary incontinence.
  • Each of the present compounds synthesized in Examples 1 and 2 was orally administered to 6-week old male ddy mice (CHARLES RIVER JAPAN) at 100 mg/kg. The fact that none of the eight animals were found to be dead showed that these compounds have a low toxicity. The other compounds, which achieved the same results, were also shown to have a low toxicity.
  • the compounds of the present invention are hovel compounds. They are expected to compounds which are unlikely to induce any side effect due to drug interactions, since they have a high human ⁇ 3-adrenoreceptor stimulating activity and a low drug metabolizing enzyme inhibiting activity. Therefore, the compounds of the present invention are useful as medicines for treating and preventing ⁇ 3-adrenoreceptor associated diseases including diabetes, obesity and hyperlipidemia. The compounds of the present invention are also useful as medicines for treating and preventing fatty liver, urinary incontinence and others.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Endoscopes (AREA)

Claims (10)

  1. Composé de formule (I) générale :
    Figure imgb0031
     ou l'un de ses sels,
    dans laquelle
    R1 représente un atome d'hydrogène, un groupe hydroxyle ou un atome d'halogène;
    R2 représente NHSO2R3 ou SO2NR4R4';
    R3 représente un groupe alkyle en C1 à C6, un groupe benzyle, un groupe phényle ou NR4R4';
    R4 et R4' peuvent être identiques ou différents et représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 ;
    R5 représente un atome d'hydrogène ou un groupe alkyle en C1 à C6 ;
    R6 et R7 peuvent être identiques ou différents et représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C6, un groupe alkyle en C1 à C6 facultativement substitué avec un ou plusieurs atomes d'halogène, un groupe -(CH2)n-phényle facultativement substitué avec un groupe hydroxyle, un atome d'halogène, un groupe trifluorométhyle, un groupe alkyle en C1 à C6, un groupe alcoxy en C1 à C6, un groupe acyle en C1 à C6, NR4R4', un NHCOalkyle en C1 à C6, NHCH2C6H5, un NHSO2-alkyle en C1 à C6, NHSO2CH2C6H5, un groupe nitro ou un groupe cyano, -CH=CH-CO2R5 Ou -(CH2)n-R8;
    R8 représente OR5, CN, NR41R41', CO2R5, SO3R5, un SO2-alkyle en C1 à C6, SO2NR41R41', C(=O)R5, C(=O)NR41R41' ou NR51COR5, où R5 est tel que défini ci-dessus ; R51 représente un atome d'hydrogène ou un groupe alkyle en C1 à C6 ; R41 et R41' peuvent être identiques ou différents et représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C6 ou un groupe cycloalkyle en C3 à C6, ou R41 et R41' pris ensemble représentent un groupe alkylène en C2 à C6 ; ou R8 est un hétérocycle choisi parmi un pyridyle, un pyrimidinyle, un pyrazinyle, un thiazolyle, un oxazolyle, un imidazolyle, un triazolyle, un 1,2,4-oxa-diazolyle, un isoxazolyle, un tétrazolyle, un pyrazolyle, un hexaméthylèneiminyle, un pipéridinyle et un pyrrolidinyle, un des atomes d'azote de cycle de l'imidazolyle, du triazolyle et du tétrazolyle pouvant être facultativement substitué avec un groupe alkyle en C1 à C6 qui est facultativement substitué avec un ou plusieurs atomes d'halogène ; dans lequel, en ce qui concerne un ou plusieurs des atomes de carbone de cycle de chaque hétérocycle, chacun d'entre eux peut être facultativement substitué avec un ou plusieurs substituants qui sont choisis indépendamment parmi un hydrogène, un groupe alkyle en C1 à C6 facultativement substitué avec un ou plusieurs atomes d'halogène, un atome d'halogène, un nitro, un cyano et - (CH2)n-R9; et dans lequel l'atome d'azote de cycle de l'hexaméthylèneiminyle, du pipéridinyle et du pyrrolidinyle peut être substitué avec un groupe alkyle en C1 à C6, un groupe cycloalkyle en C3 à C6, COR5, COOR5, CONR4R4' ou SO2R5 ;
    R9 représente NR4R4', CO2R5, C(=O)-NR4R4', OR5, SO3R5, un SO2alkyle en C1 à C6 ou SO2NR4R4' , où R5, R4 et R4' sont tels que définis ci-dessus ;
    à condition que soient exclues les combinaisons de R6 et R7 dans lesquelles R6 et R7 sont identiques ou différents et sont chacun choisis parmi un atome d'hydrogène, un groupe alkyle en C1 à C6 et un groupe -(CH2)m-phényle facultativement substitué dans lequel m est 0 ou 1 ;
    X représente NR10 ;
    Y représente un atome d'oxygène, NH, un atome de soufre ou un groupe méthylène ;
    Z1 à Z6 représentent tous un atome de carbone ;
    R10 représente un atome d'hydrogène, un groupe -(CH2)n- phényle facultativement substitué avec un groupe hydroxyle, un atome d'halogène, un groupe trifluorométhyle, un groupe alkyle en C1 à C6, un groupe alcoxy en C1 à C6, un groupe acyle en C1 à C6, NR4R4', un NHCOalkyle en C1 à C6, NHCH2C6H5, un NHSO2-alkyle en C1 à C6, NHSO2CH2C6H5, un groupe nitro ou un groupe cyano, un groupe alkyle en C1 à C10 ou -(CH2)n-R8, où R8, R4 et R4' sont tels que définis ci-dessus ;
    n est un nombre entier allant de 0 à 6 ;
    *1 représente un atome de carbone asymétrique ; et
    *2 représente un atome de carbone asymétrique quand R5 est différent d'un atome d'hydrogène.
  2. Composé selon la revendication 1 de formule (I) générale, dans lequel R8 est OR5, CN, NR41R41', CO2R5, SO3R5, un SO2-alkyle en C1 à C6, SO2NR41R41' , C(=O)R5 ou C (=O)NR41R41' , où R5 est tel que défini ci-dessus ; et R41 et R41' peuvent être identiques ou différents et représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6, ou R41 et R41' pris ensemble représentent un groupe alkylène en C2 à C6 ; ou R8 est un hétérocycle choisi parmi un pyridyle, un pyrimidinyle, un pyrazinyle, un thiazolyle, un oxazolyle, un imidazolyle, un triazolyle, un 1,2,4-oxa-diazolyle, un isoxazolyle, un tétrazolyle et un pyrazolyle, un des atomes d'azote de cycle de l'imidazolyle, du triazolyle et du tétrazolyle pouvant être facultativement substitué avec un groupe alkyle en C1 à C6 qui est facultativement substitué avec un ou plusieurs atomes d'halogène ; dans lequel, en ce qui concerne un ou plusieurs des atomes de carbone de cycle de chaque hétérocycle, chacun d'entre eux peut être facultativement substitué avec un ou plusieurs substituants qui sont choisis indépendamment parmi un hydrogène, un groupe alkyle en C1 à C6 facultativement substitué avec un ou plusieurs atomes d'halogène, un atome d'halogène, un nitro, un cyano et - (CH2)n-R9 ; dans lequel R9 est tel que défini ci-dessus, ou l'un de ses sels.
  3. Composé selon la revendication 1 ou 2 de formule (I) générale, dans lequel R1 est présent en position para (position 2) par rapport à la chaîne latérale alcool aminé, ou l'un de ses sels.
  4. Composé selon l'une quelconque des revendications 1 à 3 de formule (I) générale, dans lequel Y est un atome d'oxygène, NH ou un atome de soufre, ou l'un de ses sels.
  5. Composé selon l'une quelconque des revendications 1 à 4 de formule (I) générale, dans lequel X est NH, ou l'un de ses sels.
  6. Composé selon la revendication 1 de formule (I) générale, dans lequel R6 est l'un quelconque des groupes choisis parmi le 3-pyridyle, le 4-pyridyle, le 3-pipéridinyle, le N-tert-butoxycarbonyl-3-pipéridinyle, le 2-éthoxycarbonyléthyle, le 2-(N,N-diméthylamino-carbonyl)éthyle et le 2-acétylaminoéthyle, et R7 est un méthyle ou un éthyle.
  7. Composé selon la revendication 1 ou 6 de formule (I) générale, dans lequel R7 est un méthyle.
  8. Composé selon la revendication 1, qui est un composé choisi dans le groupe constitué par :
    le (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indole-2-carboxylate d'éthyle ;
    l'acide (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indole-2-carboxylique ;
    le (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    l'acide (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indole-3-carboxylique ;
    le (R) -N- [3- [2- [2-(3-hydroxyméthyl-2-méthyl-1H-indol-6-yloxy)éthylamino]-1-hydroxyéthyl]phényl]-méthanesulfonamide ;
    le (R) -N- [3- [2- [2- [3- (N' ,N' -diméthylamino)méthyl-2-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]-phényl]méthanesulfonamide ;
    le (R)-[6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]-acétate d'éthyle ;
    l'acide (R)- [6- [2- [2- (3-méthylsulfonylamino) -phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétique ;
    le (R)-3-[6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]-acrylate d'éthyle ;
    l'acide (R)-3-[6-[2-[2-(3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acrylique ;
    le (R)-3-[6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]-propionate d'éthyle ;
    l'acide (R)-3-[6-[2-[2-(3-méthanesulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl] propionique ;
    le (R) -N- [3- [2- [2- [3- (2-aminoéthyl) -2-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]phényl]-méthanesulfonamide ;
    le (R) -N- [3- [2- [2- [3- (2-N' ,N' -diméthylamino) éthyl-2-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]-phényl]méthanesulfonamide ;
    le (R) -N- [3- [2- [2- [3-acétyl-2-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]phényl]méthane-sulfonamide ;
    le (R)-[6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-éthyl-1H-indol-3-yl]acétate d'éthyle ;
    l'acide (R)-[6-[2-[2-(3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-éthyl-1H-indol-3-yl]acétique ;
    le (R)-[6-[2-[2-(3-méthanesulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-phényl-1H-indol-3-yl]-acétate d'éthyle ;
    l'acide (R)-[6-[2-[2-(3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-phényl-1H-indol-3-yl]acétique ;
    le (R)-[6-[2-[2-(4-chloro-3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétate d'éthyle ;
    l'acide (R)-[6-[2-[2-(4-chloro-3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétique ;
    le (R)-[6-[2-[2-(4-fluoro-3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétate d'éthyle ;
    l'acide (R)-[6-[2-[2-(4-fluoro-3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétique ;
    l'acide (R)-[6-[2-[2-(4-hydroxy-3-méthyl-sulfamoyl)phényl-2-hydroxyéthylamino]éthoxy]-2-méthyl-1H-indol-3-yl]acétique ;
    l'acide (R)-[6-[2-[2-(3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-2-(2-méthoxyéthyl)-1H-indol-3-yl]acétique ;
    l'acide (R) -3- [6- [2- [2- (3-méthylsulfonylamino) -phényl-2-hydroxyéthylamino]éthoxy]-2-(2-méthoxyéthyl)-1H-indol-3-yl]propionique ;
    le (R) -N- [3- [2- [2- [2- (2-méthoxyéthyl) -3-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]phényl]-méthanesulfonamide ;
    le (R) -N- [3- [2- [2- [3-éthyl-2- (2-méthoxyéthyl) -1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]phényl]-méthanesulfonamide ;
    le (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthylamino]-3-méthyl-1H-indole-2-carboxylate d'éthyle ;
    l'acide (R)-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthylamino]-3-méthyl-1H-indole-2-carboxylique ;
    le (R)- [6-[2-[2-(4-chloro-3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indol-2-yl]acétate d'éthyle ;
    le (R)-[6-[2-[2-(4-fluoro-3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indol-2-yl]acétate d'éthyle ;
    le (R,R)-6-[2-[2-(4-fluoro-3-méthylsulfonylamino)-phényl-2-hydroxyéthylamino]propoxy]-3-méthyl-1H-indole-2-carboxylate d'éthyle ;
    le (R) -5- [2- [2- (3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indole-2-carboxylate d'éthyle ;
    l'acide (R)-1-benzyl-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy]-1H-indole-2-carboxylique ;
    l'acide (R)-1-[3-(N'-méthylsulfonylamino)-phényl]méthyl-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxyéthylamino]éthoxy] -1H-indole-2-carboxylique
    l'acide (R)-1-[4-(N'-méthylsulfonylamino)phényl]-méthyl-6-[2-[2-(3-méthylsulfonylamino)phényl-2-hydroxy-éthylamino]éthoxyl-1H-indole-2-carboxylique ;
    le (R) -N- [3- [2- [2- (2, 3-ditrifluorométhyl-1H-indol-6-yloxy)éthylamino]-1-hydroxyéthyl]phényl]méthane-sulfonamide ;
    le (R) -N- [3- [1-hydroxy-2- [2- (3-méthyl-2-pyridin-3-yl-1H-indol-6-yloxy)éthylamino]éthyl]phényl]méthane-sulfonamide ;
    le (R) -N- [3- [2- [2- (3-éthyl-2-pyridin-3-yl-1H-indol-6-yloxy)éthylamino]-1-hydroxyéthyl]phényl]-méthanesulfonamide ;
    le (R) -N- [3- [1-hydroxy-2- [2- (3-méthyl-2-pyridin-4-yl-1H-indol-6-yloxy)éthylamino]éthyl]phényl]méthane-sulfonamide ;
    le (R) -N- [3- [2- [2- [2- (N' -tert-butoxycarbonyl-pipéridin-3-yl)-3-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]phényl]méthanesulfonamide ;
    le (R) -N- [3- [2- [1-hydroxy-2- (3-méthyl-2-pipéridin-3-yl-1H-indol-6-yloxy)éthylamino]éthyl]phényl]méthane-sulfonamide ;
    le (R)-N-[3-[2-[2-[3-(2-acétylaminoéthyl)-2-méthyl-1H-indol-6-yloxy]éthylamino]-1-hydroxyéthyl]-phényl]méthanesulfonamide ;
    le (R)-3-[6-[2-[2-hydroxy-2-(3-méthylsulfonyl-aminophényl)éthylamino]éthoxy]-3-phényl-1H-indol-2-yl]propionate d'éthyle ;
    le (R) -N- [2-fluoro-5- [1-hydroxy-2- [2- (3-méthyl-2-pyridin-3-yl-1H-indol-6-yloxy)éthylamino]éthyl]phényl]-méthanesulfonamide ;
    le (R)-3-[6-[2-[2-(4-fluoro-3-méthylsulfonylamino-phényl)-2-hydroxyéthylamino]éthoxy]-3-méthyl-1H-indol-2-yl]propionate d'éthyle ;
    le (R)-3-[3-méthyl-6-[2-[2-(3-méthylsulfonylamino-phényl)-2-hydroxyéthyl]amino]éthoxy]-1H-indol-2-yl]-N,N-diméthylpropionamide ;
    le (R)-3-[3-méthyl-6-[2-[2-(3-méthylsulfonylamino-phényl)-2-hydroxyéthylamino]éthoxy] -1H-indol-2-yl]-propionate d'éthyle ; et
    le (R)-2-[3-méthyl-6-[2-[2-(3-méthylsulfonylamino-phényl)-2-hydroxyéthylamino]éthoxy]-1H-indol-2-yl]-acétate d'éthyle,
    ou l'un de leurs sels.
  9. Médicament comprenant un composé selon la revendication 1 ou l'un de ses sels en tant qu'ingrédient actif.
  10. Médicament selon la revendication 9, dans lequel le médicament est destiné au traitement ou à la prévention du diabète, de l'obésité, de l'hyperlipidémie ou de l'incontinence urinaire.
EP08005358A 2001-10-25 2002-10-25 Composés bicycliques Expired - Lifetime EP1935882B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001327467 2001-10-25
EP02770271A EP1447400B1 (fr) 2001-10-25 2002-10-25 Compose bicyclique

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP02770271.1 Division 2002-10-25
EP02770271A Division EP1447400B1 (fr) 2001-10-25 2002-10-25 Compose bicyclique

Publications (2)

Publication Number Publication Date
EP1935882A1 EP1935882A1 (fr) 2008-06-25
EP1935882B1 true EP1935882B1 (fr) 2011-02-09

Family

ID=19143688

Family Applications (2)

Application Number Title Priority Date Filing Date
EP02770271A Expired - Lifetime EP1447400B1 (fr) 2001-10-25 2002-10-25 Compose bicyclique
EP08005358A Expired - Lifetime EP1935882B1 (fr) 2001-10-25 2002-10-25 Composés bicycliques

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP02770271A Expired - Lifetime EP1447400B1 (fr) 2001-10-25 2002-10-25 Compose bicyclique

Country Status (14)

Country Link
US (3) US7271190B2 (fr)
EP (2) EP1447400B1 (fr)
JP (1) JP4492848B2 (fr)
KR (1) KR100622461B1 (fr)
CN (1) CN100347158C (fr)
AT (2) ATE408598T1 (fr)
AU (1) AU2002336311B8 (fr)
CA (1) CA2464367C (fr)
DE (2) DE60228990D1 (fr)
DK (1) DK1447400T3 (fr)
ES (1) ES2309200T3 (fr)
HK (1) HK1072770A1 (fr)
PT (1) PT1447400E (fr)
WO (1) WO2003035620A1 (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60228990D1 (de) * 2001-10-25 2008-10-30 Asahi Kasei Pharma Corp Bicyclische verbindung
ATE445399T1 (de) 2004-03-22 2009-10-15 Lilly Co Eli Pyridyl-derivate und ihre verwendung als mglu5- rezeptorantagonisten
EP1734963A4 (fr) 2004-04-02 2008-06-18 Merck & Co Inc Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
DE102004021779A1 (de) * 2004-04-30 2005-11-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
WO2006112549A1 (fr) * 2005-04-20 2006-10-26 Takeda Pharmaceutical Company Limited Compose heterocyclique fusionne
WO2006132196A1 (fr) * 2005-06-08 2006-12-14 Asahi Kasei Pharma Corporation PRODUIT PHARMACEUTIQUE ORIGINAL COMPRENANT UN AGONISTE β3
DE102005052127A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue indol-haltige Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052103A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052101A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052102A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE112009001036B4 (de) * 2008-06-06 2013-12-24 Mitsubishi Electric Corp. Bord-Funkkommunikationssystem
AR072297A1 (es) 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.
WO2010041568A1 (fr) 2008-10-09 2010-04-15 旭化成ファーマ株式会社 Dérivé d’indazole
EP2345644A4 (fr) * 2008-10-09 2012-03-21 Asahi Kasei Pharma Corp Composé d indazole
US20100222404A1 (en) * 2008-11-04 2010-09-02 Asahi Kasei Pharma Corporation Indazole derivative dihydrochloride
AU2010301450A1 (en) * 2009-09-30 2012-04-19 Asahi Kasei Pharma Corporation Indazole analogue
AU2011245499B2 (en) * 2010-04-30 2014-09-25 Merck Sharp & Dohme Corp. Novel beta 3 adrenergic receptor agonists
CN106986862A (zh) 2010-12-22 2017-07-28 Abbvie 公司 丙型肝炎抑制剂及其用途
CN108191845A (zh) * 2018-02-12 2018-06-22 李化绪 一种异恶唑亚氨基类化合物及其在降血脂药物中的应用

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1041523A (fr) 1974-06-19 1978-10-31 Queen's University Preparation d'oxapenicilline-1 et nouveaux produits intermediaires que l'on peut en tirer
FR2332010A1 (fr) 1975-11-18 1977-06-17 Continental Pharma Amino-alcool heterocyclique, son sel et son procede de preparation
DE2833140A1 (de) 1978-07-28 1980-02-07 Boehringer Sohn Ingelheim Neue n-substituierte heterocyclen
JPS5553262A (en) 1978-10-17 1980-04-18 Yamanouchi Pharmaceut Co Ltd Phenylethanolamine derivative
US4338333A (en) 1979-06-16 1982-07-06 Beecham Group Limited Ethanamine derivatives their preparation and use in pharmaceutical compositions
JPS5950671B2 (ja) 1982-08-26 1984-12-10 山之内製薬株式会社 フェニルエタノ−ルアミン誘導体およびその製造法
GB8419797D0 (en) 1984-08-03 1984-09-05 Beecham Group Plc Compounds
US5061727A (en) 1990-05-04 1991-10-29 American Cyanamid Company Substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles
PL312005A1 (en) * 1993-06-14 1996-04-01 Pfizer Binary amines as antidiabetic and antiobesitic agents
US5776983A (en) 1993-12-21 1998-07-07 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
IL113410A (en) 1994-04-26 1999-11-30 Merck & Co Inc Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them
JPH08165276A (ja) 1994-12-14 1996-06-25 Dainippon Pharmaceut Co Ltd ２−アルキルアミノ−１−フェニルエタノール誘導体
EP0828712A1 (fr) 1995-05-10 1998-03-18 Pfizer Inc. Agonistes du recepteur beta-adrenergique
CA2242351C (fr) * 1996-01-10 2003-03-11 Asahi Kasei Kogyo Kabushiki Kaisha Nouveaux composes tricycliques et compositions medicamenteuses contenant ces composes
US5859044A (en) 1996-07-31 1999-01-12 Pfizer Inc. β-adrenergic agonists
AU735249B2 (en) * 1997-07-03 2001-07-05 Asahi Kasei Kabushiki Kaisha Novel tricyclic compounds having saturated rings and medicinal compositions containing the same
WO2000035890A1 (fr) 1998-12-15 2000-06-22 Asahi Kasei Kabushiki Kaisha Nouveaux composes heterocycliques et compositions de medicaments les renfermant
TW519537B (en) 1999-03-26 2003-02-01 Asahi Chemical Ind Process for the preparation of tricylic amino-alcohol derivatives
AU3551000A (en) 1999-03-31 2000-10-23 Albert Hedegard Storage container for a tractor
KR20020005648A (ko) * 1999-04-01 2002-01-17 야마모토 카즈모토 삼환성 아미노알콜 유도체의 아지드를 경유하는 제조법
CA2394778A1 (fr) 1999-12-16 2002-06-14 Shiro Miyoshi Nouveaux composes tricycliques substitues
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
WO2001083453A1 (fr) 2000-04-28 2001-11-08 Asahi Kasei Kabushiki Kaisha Nouveaux composes tricycliques substitues
AU5257401A (en) 2000-04-28 2001-11-12 Asahi Chemical Ind Novel bicyclic compounds
AU2001252575A1 (en) 2000-04-28 2001-11-12 Asahi Kasei Kabushiki Kaisha Novel tricyclic compounds
EP1403255A4 (fr) 2001-06-12 2005-04-06 Sumitomo Pharma Inhibiteurs de rho kinase
DE60228990D1 (de) * 2001-10-25 2008-10-30 Asahi Kasei Pharma Corp Bicyclische verbindung

Also Published As

Publication number Publication date
EP1447400B1 (fr) 2008-09-17
DE60228990D1 (de) 2008-10-30
US7511069B2 (en) 2009-03-31
US7598284B2 (en) 2009-10-06
AU2002336311B8 (en) 2009-04-23
CN1606544A (zh) 2005-04-13
HK1072770A1 (en) 2005-09-09
AU2002336311B2 (en) 2009-04-02
CA2464367C (fr) 2010-10-19
DK1447400T3 (da) 2008-12-08
PT1447400E (pt) 2008-12-19
CN100347158C (zh) 2007-11-07
JPWO2003035620A1 (ja) 2005-02-10
KR20040047946A (ko) 2004-06-05
US20080076815A1 (en) 2008-03-27
DE60239170D1 (de) 2011-03-24
ATE497948T1 (de) 2011-02-15
EP1447400A1 (fr) 2004-08-18
US20050020602A1 (en) 2005-01-27
EP1447400A4 (fr) 2005-11-09
WO2003035620A1 (fr) 2003-05-01
ATE408598T1 (de) 2008-10-15
CA2464367A1 (fr) 2003-05-01
EP1935882A1 (fr) 2008-06-25
US7271190B2 (en) 2007-09-18
US20080015242A1 (en) 2008-01-17
ES2309200T3 (es) 2008-12-16
KR100622461B1 (ko) 2006-09-19
JP4492848B2 (ja) 2010-06-30

Similar Documents

Publication Publication Date Title
US7598284B2 (en) Indazole compounds as B3 adrenoceptor agonist
EP1277736B1 (fr) Nouveaux composes bicycliques
EP2595952B1 (fr) Agonistes de gpr40
US7507841B2 (en) Cannabinoid receptor modulator
KR101396606B1 (ko) 신규 갑상선 호르몬 β 수용체 작동약
US6469043B1 (en) Sulfonamide-containing indole compounds
EP3693358B1 (fr) Composé hétéroaryle contenant de l'azote, et son utilisation pharmaceutique
EP3943083A1 (fr) Inhibiteur à petites molécules de pd-1/pd-l1, composition pharmaceutique de celui-ci avec un anticorps pd-l1, et son application
CN118382622A (zh) 作为kat6抑制剂的化合物
JP4749335B2 (ja) イミダゾピリジン化合物
WO2016104451A1 (fr) Nouveau dérivé hétérocyclique
JP2009505953A (ja) リパーゼに媒介される疾患の処置のための化合物
CN115215821A (zh) 木脂素衍生物、其制备方法及用途
EP2802563B1 (fr) Nouveaux dérivés d'hétéroarylamide possédant des propriétés antiandrogéniques
EP1506180A1 (fr) Derive de thiazolidine-4-one, procede d'elaboration, et composition pharmaceutique a base de ce derive
JPH07103089B2 (ja) フェノキシ酢酸誘導体およびこれを含有する医薬製剤
JP2005504823A (ja) 神経栄養剤としてのトリアゼピン誘導体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AC Divisional application: reference to earlier application

Ref document number: 1447400

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

17P Request for examination filed

Effective date: 20080714

17Q First examination report despatched

Effective date: 20081015

RIN1 Information on inventor provided before grant (corrected)

Inventor name: OGAWA, KOHEI

Inventor name: MIYOSHI, SHIRO

AKX Designation fees paid

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 1447400

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: ASAHI KASEI PHARMA CORPORATION

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60239170

Country of ref document: DE

Date of ref document: 20110324

Kind code of ref document: P

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60239170

Country of ref document: DE

Effective date: 20110324

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20110209

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110520

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110510

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110609

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110509

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20111110

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20111103

Year of fee payment: 10

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60239170

Country of ref document: DE

Effective date: 20111110

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111031

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111031

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111031

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111025

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111025

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20121025

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130501

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121025

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60239170

Country of ref document: DE

Effective date: 20130501

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110209